title: E-cadherin expression on human carcinoma cell affects trastuzumab-mediated antibody-dependent cellular cytotoxicity through killer cell lectin-like receptor G1 on natural killer cells.
abstract: Trastuzumab is a recombinant antibody drug that is widely used for the treatment of HER2-overexpressing breast carcinoma. Despite encouraging clinical results, many HER2-overexpressing carcinomas are primarily resistant to trastuzumab. We attempted to explain trastuzumab resistance and search for solutions. Since the killer cell lectin-like receptor G1 (KLRG1), an inhibitory receptor expressed on subsets of natural killer (NK) cells recognizes E-cadherin as ligands and may inhibit immune responses by regulating the effector function of NK cells, we used HER2-overexpressing carcinoma cells which were expressing E-cadherin to investigate the role of antibody-dependent cellular cytotoxicity (ADCC) through KLRG1 on NK cells in vitro and vivo. The results indicated that HER2-overexpressing carcinoma cells were killed by trastuzumab-mediated ADCC and the ADCC activity was reflected the degree of E-cadherin expression on carcinoma cells. We found that expression of E-cadherin was shown to be a predictor of response to trastuzumab-based treatment for HER2-overexpressing carcinomas, furthermore, trastuzumab-mediated ADCC was markedly enhanced by KLRG1-negative peripheral blood mononuclear cells (PBMCs(KLRG1(-))).
authors.affiliation: Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Chisako
authors.initials: C
authors.lastname: Yamauchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.forename: Taichi
authors.initials: T
authors.lastname: Kimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.forename: Noriaki
authors.initials: N
authors.lastname: Wada
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mukai
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D015820:Cadherins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011971:Receptors, Immunologic; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015820:Cadherins; D037181:Lectins, C-Type; D018719:Erb-b2 Receptor Tyrosine Kinases; D011971:Receptors, Immunologic; D015534:Trans-Activators; D000068878:Trastuzumab; C113413:KLRG1 protein, human